Project 2 (Transmission Correlates) will characterize the biological, viral, and host correlates of HIV sexual transmission. The Clinical and Specimen Core will identify study subjects and provide the blood and genital secretion specimens for the research projects. Project 1 (Transmission Probability) will ascertain rates of transmission and generate epidemiological and behavioral data. The Administrative Core will coordinate these activities together with data management, and provide the statistical and analytical resources to permit robust and valid conclusions regarding the data. Aim 1 of Project 2 will measure the biologic correlates of sexual transmission of HIV. These include viral loads in blood and the genital tract, lymphocyte numbers in genital secretions, and the presence of viral and bacterial sexually transmitted infections. This aim will also address whether sexually transmitted HIV infection is mediated by cell-free virus or by virus-infected lymphocytes. Aim 2 will assess the viral correlates of sexual transmission of HIV. Extensive nucleotide sequencing will extend our published observations characterizing virus in the genital compartment. The objective will be to characterize the genotypic and phenotypic characteristics of transmitted HIV-1 variants. Aim 3 will investigate host determinants of sexual transmission of HIV. We will extend our studies of the neutralizing antibody response to HIV infection by determining the role of neutralizing antibody in blood and the genital tract in selecting for transmitted viral variants. The other two components of the aim will leverage our well characterized study subjects and their clinical specimens with two internationally recognized laboratories with longstanding collaborations with our group. Dr. Sunil Ahuja from the University of Texas Health Sciences Center will characterize the host genetics of both index subjects and their transmitting partners. Drs. Walker, Allen, and Altfeld from Harvard Medical School will provide full length HIV genome sequencing, viral phenotype, and CTL analyses that will characterize the role of cell mediated immunity, escape, and fitness. Each of these Aims is designed to address specific hypotheses. The data collected in Project 2, together with the epidemiologic and behavioral data from Project 1, will permit comprehensive analyses to determine which parameters are confounding, dependent, or independent determinants of HIV sexual transmission. These insights should provide important leads into the design of better vaccine candidates and other preventive strategies.